The molecular mechanisms that lead to increased restenosis in T2DM are unknown. Vascular smooth[unreadable] muscle cell (VSMC) proliferation plays a key role in restenosis following vascular injury, and glucose, insulin,[unreadable] and oxidative stress increase VSMC growth. Moreover, in animal models of T2DM, there is increased[unreadable] VSMC proliferation in response to injury. Leukocyte type 12/15 lipoxygenase (12LO) has been implicated[unreadable] as a key mediator of enhanced VSMC proliferation and neointimal formation in response to injury in animal[unreadable] models of T2DM. Our preliminary data clearly demonstrates that 12LO regulates VSMC growth, one[unreadable] potential mechanism for the accelerated response to injury in diabetes. We further demonstrate that 12LO-induced[unreadable] proliferation of VSMC is mediated by the helix-loop-helix transcription factor Id3 (a key regulator of[unreadable] insulin and glucose mediated gene transcription). We have demonstrated in multiple models of insulin[unreadable] resistance and type 2 DM, that Id3 expression is significantly increased. Mechanistic studies demonstrate[unreadable] that Id3 promotes G1-S transition leading to increased VSMC growth and that phosphorylation of Id3 on[unreadable] serine 5 regulates this event. In this renewal application, we propose to extend our in vitro mechanistic[unreadable] findings and previous in vivo expression studies to demonstrate that the 12LO/ld3 pathway is a key mediator[unreadable] of the vascular response to injury in vivo in animals models of type 2 DM. Furthermore, we propose to[unreadable] identify the cis and trans-acting elements that mediate 12LO-induced increases in Id3 expression and[unreadable] VSMC growth and confirm their role in vivo in the response to injury in T2DM .[unreadable] Hypotheses: Type 2 DM modulates the response to vascular injury via regulation of Id3 expression and[unreadable] activity and VSMC growth. This effect is mediated by 12LO-induced nuclear factor expression leading to[unreadable] enhanced Id3 expression and/or serine 5 phosphorylation of Id3. To extend our exciting findings from[unreadable] VSMC culture studies in vivo in an animals model of vascular response to injury in T2DM and to address this[unreadable] central hypothesis, we propose the following aims. Aim 1: Establish the essential role of Id3 in the[unreadable] accelerated neointimal formation in response to injury in diet-induced mouse models of type 2 DM.[unreadable] Aim 2: Evaluate in vivo the 12LO/ld3 pathway leading to accelerated VSMC growth and lesion formation.[unreadable] Aim 3c. Extend in vitro findings in vivo to confirm that the 12LO-response elements in the Id3 promoter[unreadable] required for Id3 transcription in culture also regulate Id3 transcription in vivo in response to injury in T2DM.